Cowpea Mosaic Virus Nanoparticles for Cancer Imaging and Therapy
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Advanced Drug Delivery Reviews 145 (2019) 130–144 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Cowpea mosaic virus nanoparticles for cancer imaging and therapy Perrin H. Beatty, John D. Lewis ⁎ Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada article info abstract Article history: Nanoparticle platforms are particularly attractive for theranostic applications due to their capacity for Received 16 June 2018 multifunctionality and multivalency. Some of the most promising nano-scale scaffold systems have been co- Received in revised form 7 December 2018 opted from nature including plant viruses such as cowpea mosaic virus (CPMV). The use of plant viruses like Accepted 15 April 2019 CPMV as viral nanoparticles is advantageous for many reasons; they are non-infectious and nontoxic to humans Available online 17 April 2019 and safe for use in intravital imaging and drug delivery. The CPMV capsid icosahedral shape allows for enhanced fi Keywords: multifunctional group display and the ability to carry speci c cargoes. The native tropism of CPMV for cell- Cancer therapy surface displayed vimentin and the enhanced permeability and retention effect allow them to preferentially ex- Cowpea mosaic virus travasate from tumor neovasculature and efficiently penetrate tumors. Furthermore, CPMVs can be engineered CPMV via several straightforward chemistries to display targeting and imaging moieties on external, addressable res- Drug delivery idues and they can be loaded internally with therapeutic drug cargoes. These qualities make them highly effec- eCPMV tive as biocompatible platforms for tumor targeting, intravital imaging and cancer therapy. Intravital imaging © 2019 Published by Elsevier B.V. Molecular targeting Non-invasive imaging Multifunctional Virus-like particle Contents 1. Introduction.............................................................. 131 2. Characteristicsofthecowpeamosaicvirus................................................. 131 2.1. CPMVbiocontainment,biodistributionandpathology........................................ 132 2.2. Chemicalbioconjugation..................................................... 134 2.3. ShieldingofCPMVnanoparticlesforincreasedbioretention...................................... 136 2.4. Geneticengineeringtointroducefunctionality............................................ 136 2.5. ProductionofCPMVandCPMVvirus-likeparticles.......................................... 136 3. TherapeuticandtheranosticusesofCPMVs................................................ 137 3.1. Tumorhomingpeptides...................................................... 137 3.2. Cargoloading.......................................................... 137 3.3. Photodynamic therapy using CPMV-C60 fullereneconjugates..................................... 138 3.4. UseofCPMVasavaccineincancerimmunotherapy......................................... 138 4. Intravitalvascularimagingfornon-invasivecancerdetection........................................ 139 4.1. Chickembryonicchorioallantoicmembranemodels......................................... 139 4.2. Deep tissue imaging using CPMVs decorated with multivalent fluorescentdyes............................. 139 4.3. NativetropismofCPMVforvimentinonhostcells.......................................... 140 4.4. CPMVtargetedtogastrin-releasingpeptidereceptors........................................ 141 4.5. Neovascularimagingviavascularendothelialgrowthfactorreceptor(VEGFR)targeting.........................141 4.6. Neovascularimagingviaepidermalgrowthfactor-likedomain7(EGFL7)proteintargeting....................... 141 5. Conclusionsandfuturedirections..................................................... 142 Acknowledgements............................................................. 142 References.................................................................. 142 ⁎ Corresponding author at: Translational Prostate Cancer Research Group, Department of Oncology, University of Alberta, 5-142C Katz Group Building, 114th St and 87th Ave, Edmonton AB T6G 2E1, Canada. E-mail address: [email protected] (J.D. Lewis). https://doi.org/10.1016/j.addr.2019.04.005 0169-409X/© 2019 Published by Elsevier B.V. P.H. Beatty, J.D. Lewis / Advanced Drug Delivery Reviews 145 (2019) 130–144 131 1. Introduction Table 1 Advantageous features of CPMV for use in tumor cell imaging and therapy. Many different scaffold and carrier systems have been co-opted from Features Measurement or description Reference nature, or synthetically designed for use in tumor cell-specific imaging Non-pathogenic and Dosages up to 100 mg/kg body weight in [23,27] – and drug delivery (reviewed in [1 7]). Naturally-occurring scaffold- non-toxic mice (1016 CPMVs) are nontoxic. carriers include viral nanoparticles (VNP) and self-assembling protein Biodistribution After dosing in mice, found in various organs, [40,47] cages [7–13]. VNPs such as temperate filamentous bacteriophage (M13, culminating in the liver and spleen. fd), lytic capsid and tailed bacteriophage (T4, P22, λ etc.) or plant viruses; Biocompatible and CPMV were retained for 72 h in chick embryo [23] long retention endothelium system and in mice for 1 to brome mosaic virus (BMV), red clover necrotic mosaic virus (RCNMV), several days. potato virus X (PVX), tobacco mosaic virus (TMV), cowpea chlorotic Biodegradable CPMVs do not persist in vivo, therefore they [55] mottle virus (CCMV), cowpea mosaic virus (CPMV) and mammalian vi- are good candidates for therapeutic use. ruses; canine parvovirus (CPV), influenza A and hepatitis B have been Physical and chemical Temperature: up to 60C, pH range 3 to 9, [7,33,40] stability organic solvents such as dimethyl sulfoxide, used as scaffolds and cargo-carriers in cancer research [7,9–11,14–18]. resistant to proteolysis and gastric and Supramolecular, self-assembled protein cages such as heat shock protein intestinal conditions. (Hsp), ferritin, and vault have also been utilized as drug delivery nano- High resolution and Dye-labelled CPMV nanoparticles did not [23] particles [8,19]. In addition, medically relevant, organic and inorganic non-aggregating aggregate, allowing for high resolution synthetic nanoparticles have been designed; nanobombs, nanoworms, imaging. Fully characterized RNA-1 and -2 genomes and gene products [32,57,118] micelles, liposomes, dendrimers, dendrons, superparamagnetic iron sequenced and annotated. X-ray oxide nanoparticles, gold nanoparticles and quantum dots [5,20–22]. Al- crystallography and cryogenic electron though these various carriers differ in shape and macromolecular com- microscopy done on capsid ponents they share three essential features; (1) consist of uniform size In vivo production of CPMVs with encapsidated RNA genomes. [7] CPMV High yield: 0.8 to 1.0 mg CPMV per g infected distribution within their type, (2) act as molecular scaffolds to display cowpea leave tissue different functional moieties, and (3) act as drug delivery vehicles due In vitro production of CPMV VLPs via trans expression of L-S [28,82,89] to their internal cargo carrying capacity [5,7]. Possibly the largest advan- eCPMV subunit fusion protein and 24 K protease in tage of using any of these nanoparticles in cancer research, diagnosis and cowpea protoplasts or insect cells. High therapy is their multifunctionality. Nanoparticles, including VNPs like yield: 1 g pure eCPMV per kg fresh-weight N. benthamiana leaf tissue CPMV, can simultaneously display imaging probes, targeting or homing Ease of Synthesis and purification of dye-labelled [57] moieties and carry a chemotherapy drug as cargo for maximum anti- functionalization CPMV nanoparticles in one day, using either cancer activity [5]. For example, non-invasive, intravital, vascular imag- standard or click chemistry ing has been problematic as a tumor detection and diagnostic tool External conjugation 60 asymmetrical protein units per capsid [33,57] because of inadequate resolution and poor fluorescent dye tissue pene- with, lysine with 5 solvent-exposed lysine residues per residues protein unit, providing a total of 300 tration [23]. However, the VNP scaffold multifunctionality allows for potential conjugation sites per nanoparticle. high density display of fluorescent dye molecules and targeting ligands Single functional CPMV labelled with multiple copies of a [57] simultaneously with the ease of VNP extravasation through leaky group display single functional group (e.g. 120 copies of fl tumor blood vessels [24]. The fluorescent nanoparticles remain bright, uorescent dye) made with no detriment to the signal. without detectable quenching, which increases the resolution, and can Multiple functional CPMV labelled with single copies of multiple [57] target deep tissue vascular endothelial cells for up to 72 h [23,25]. group display functional groups made with no detriment to Which carrier system to use for tumor imaging and or drug delivery targeting. depends on the physiochemical and pharmacokinetic properties of the Native tropism WT-CPMV nanoparticles bind to vimentin on [112] carrier, biological distribution of the tumor, immunogenicity between endothelial cells Internal conjugation The thiol side chains of 2 cysteine residues [112] the carrier and host, and the ratio of toxicity between host diseased are ligation handles for internal conjugation. cells to host healthy cells. Cargo loaded capsid 130 to 155 dye or drug molecules per CPMV [27] There are many features of CPMV nanoparticles